Enhancing Sympathetic Outflow Control Following Spinal Cord Injury Using Targeted Plasticity Therapy

摘要 几乎所有的交感神经流出控制通路都通过脊髓影响周围组织。 颈脊髓损伤影响交感神经流出控制，导致几个衰弱的缺陷（此外， 瘫痪），包括无法将血液重新分配到活动组织和肌肉疲劳。目前有 颈髓损伤后交感神经流出控制功能障碍尚无持续有效的治疗方法 损伤这项研究的长期目标是使用迷走神经刺激配对来解决这一重大差距。 颈髓损伤后进行康复治疗以增强交感神经流出控制。配对迷走神经 在康复过程中用运动刺激神经导致可塑性增强的快速释放， 神经调节剂，导致运动控制系统的重组。这项建议的目的是 确定迷走神经刺激与康复配对对交感神经流出控制的具体影响 cSCI后，并确定有助于这些影响的神经通路。我们还将评估 迷走神经刺激的递送方案（有或没有康复）。我们的核心假设是迷走神经 神经刺激与康复期间的运动精确配对， 交感神经流出控制回路，从而改善运动耐力和肌肉抗疲劳性 CSCI之后。我们将通过三个具体目标来评估这一假设：1）确定迷走神经的影响 刺激与康复配对对前肢肌肉和心血管功能;并测量 2)皮层和3）皮层下可塑性相关的交感神经流出控制。我们将通过以下方式实现这些目标： 多学科评估，利用电生理学和神经解剖学技术。拟议 这项研究意义重大，因为它将确定迷走神经刺激与康复配对是否是一种可行的治疗方法 用于治疗颈脊髓损伤后的交感神经控制功能障碍。此外，这些结果将 阐明前肢功能、交感神经流出控制、迷走神经 刺激疗法和神经可塑性。

Abstract Almost all sympathetic outflow control pathways travel through the spinal cord for affecting the peripheral tissues. Cervical spinal cord injury impacts sympathetic outflow control, leading to several debilitating deficits (in addition to paralysis), including an inability to redistribute blood to active tissues and muscle fatigue. There are currently no consistently effective treatments for sympathetic outflow control dysfunction following cervical spinal cord injury. The long-term goal of this research is to address this significant gap using vagus nerve stimulation paired with rehabilitation to enhance sympathetic outflow control following cervical spinal cord injury. Pairing vagus nerve stimulation with movements during rehabilitation leads to the rapid release of plasticity enhancing neuromodulators, leading to the reorganization of motor control systems. The objective of this proposal is to determine the specific effects of vagus nerve stimulation paired with rehabilitation on sympathetic outflow control following cSCI, and determine the neural pathways contributing to these effects. We will also assess the optimal delivery regime for vagus nerve stimulation (with or without rehabilitation). Our central hypothesis is that vagus nerve stimulation precisely paired with movements during rehabilitation enhances the plasticity of spared sympathetic outflow control circuits, leading to improved motor endurance and muscle fatigue resistance following cSCI. We will assess this hypothesis via three specific aims: 1) determine the effects of vagus nerve stimulation paired with rehabilitation on forelimb muscle and cardiovascular function; and measure changes in 2) cortical and 3) subcortical plasticity related to sympathetic outflow control. We will pursue these aims using multidisciplinary assessments, leveraging electrophysiological and neuroanatomical techniques. The proposed research is significant, as it will determine if vagus nerve stimulation paired with rehabilitation is a viable therapy for treating sympathetic control dysfunction following cervical spinal cord injury. Furthermore, these results will elucidate the critical relationships between forelimb function, sympathetic outflow control, vagus nerve stimulation therapy, and neuroplasticity.